A Clinical Measure of DNA Methylation Predicts Outcome in De Novo AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2591-2591
Author(s):  
Marlise R. Luskin ◽  
Phyllis Gimotty ◽  
Catherine Smith ◽  
Alison Loren ◽  
Maria Figueroa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Board Of Directors ◽  
Prognostic Value ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Advisory Committees ◽  
Recurrent Mutations ◽  
The Mean ◽  
De Novo Aml

Abstract Background: Despite advances, the majority of patients (pts) with acute myeloid leukemia (AML) will die of their disease. Current genetics-based risk classification schemes inadequately predict outcome. We sought to determine if a novel methylation-based biomarker could enhance risk stratification in AML. Methods: Using a novel methylation assay (xMELP) validated for the clinical laboratory, we performed DNA methylation assessment at 17 previously identified prognostic loci to calculate a summary methylation statistic (M-score, Wertheim et al. Clin Chem 2015) for 166 pts with de novo AML treated at the University of Pennsylvania (UPENN). Targeted next-generation sequencing (NGS) of 33 hematologic malignancy-associated genes was performed for a 136 pt subset. The association of M-score with other prognostic variables and outcome [complete remission (CR) and overall survival (OS)] was evaluated. Median follow-up was 68.1 mos (range 1.4-150.2) among 38 survivors and 10.5 mos (range 0.1-95.2) among those (n=128) deceased. The optimal M-score for identifying groups with differing OS in the total UPENN cohort defined a binary classifier. The classifier was validated in UPENN subgroups and in a separate ECOG ACRIN E1900 trial cohort. Results: The mean and median M-score for the UPENN cohort was 92.3 (95% confidence interval [CI], 87.4-97.2) and 91.4 (range, 30.8-97.3), respectively; the M-score was not significantly associated with age, gender, specimen type, blast percent, NPM1, or FLT3-ITD. Patients with favorable cytogenetics had a lower mean M-score than those with non-favorable cytogenetics; there was no difference between intermediate and unfavorable cytogenetic groups. Univariate analyses demonstrated that a 10-unit increase in M-score was associated with a 10% increase in the hazard of death (HR 1.1; P<.0001) and a 20% increase in the odds of failing to achieve CR (OR 1.2, P<.0001). In multivariable Cox analysis, higher M-score (HR 1.1, P=.011) and older age (P=.001) were significantly associated with increased hazard of death, while NPM1+/FLT3-ITD-status (P=.031) was associated with decreased hazard of death. In a multivariable logistic analysis, higher M-score (HR, 1.1, P=.034) and older age (P=.007) were associated with increased odds of failing to achieve CR, while favorable cytogenetics (P=.030) was associated with achievement of CR. Based on the maximization of the log-rank statistic, the optimal M-score cutpoint was 86, which defined a binary risk classifier (hazard of death for high vs low M-score: unadjusted HR 2.5, P<.0001; adjusted HR 1.9, P=.003). Median OS was 26.6 vs. 10.6 mos for low and high M-score groups (Figure). The CR rates for low and high M-score groups were 84% and 61%, respectively. The performance of the M-score classifier was confirmed in pts ≤ 60 yrs with intermediate cytogenetics (log-rank P=.001, OS in high vs low M-score groups: 36.4 vs 14.0 mos) and among pts who achieved CR with initial therapy (log-rank P<.00001, OS 43.9 vs 17.2 mos). The M-score classifier identified groups with different outcome regardless of allogeneic transplant. The M-score classifier was validated in the E1900 cohort (n=383). The mean and median M-scores were similar to the UPENN cohort and M-score was significantly associated with OS on multivariable analysis (P<0.0001). The M-score classifier identified E1900 subgroups with different OS (log-rank P<.00001; OS 29.5 vs 12.6 mos), a finding confirmed in the intermediate cytogenetics group, in those aged <50 and ≥50 yrs, and among pts assigned to both standard and high dose daunorubicin. Notably, high dose daunorubicin benefited patients with high M-scores (P=.001), but not those with low M-scores (P=.328). We also evaluated the prognostic value of the M-score in the context of an extended molecular profile. Random forest analysis of the UPENN cohort showed that M-score and age are the most robust predictors of OS, while a subset of recurrent mutations (FLT3-ITD, NPM1, IDH2, TET2, TP53, NRAS, CEBPA) also contribute to prognosis, but to a lesser degree. Conclusion: The M-score and associated classifier represent promising tools for clinical decision-making in AML and deserve further investigation. The prognostic value of the M-score may be superior to mutational analysis. Optimal methods for integration of M-score, clinical and genetic information are being defined. Figure 1. Figure 1. Disclosures Loren: Merck: Research Funding. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

Changes in the Hierarchy of Risk Factors with Older Age in De-Novo Acute Myeloid Leukemia (AML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1977-1977
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Claudia Schoch ◽  
Torsten Haferlach ◽  
Hubert L. Serve ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Complete Remission ◽  
De Novo ◽  
Older Age ◽  
High Dose ◽  
Age Group ◽  
Risk Profiles ◽  
Age Related ◽  
De Novo Aml

Abstract After recent reports addressed prognostic factors and outcome in older age AML (Burnett et al. Blood106:162a,2005; Wheatley et al. Blood106:199a,2005; Appelbaum et al. Blood107:3481–5,2006; Farag et al. Blood108:63–73,2006) we evaluated 764 patients of 60–85 (median 66) years reduced to those with de-novo AML, known karyotype, and identical consolidation-maintenance chemotherapy, who were part of the 1992 and 1999 multicenter randomized trials by the German AMLCG (Buchner et al. J Clin Oncol21:4496–504,2003;24:2480–9,2006). 521 patients were 60 -< 70 (median 64) and 243 patients were 70–85 (median 73) years of age. 64% and 50% patients respectively went into complete remission, 24% and 29% remained with persistent AML, 12% and 21% succumbed to early and hypoplastic death (p<.001). The overall survival in the younger (60- < 70y) and older (70+) patients was at a median of 13 vs 6 months and 18% vs 8% survived at 5 years (p<.001). Once in complete remission, the remission duration was 14 vs 12 months (median) and equally 18% at 5 years; the relapse-free survival is 13 vs 11 months (median) and 14% vs 13% at 5 years. While all patients were randomized up-front for 2 versions of induction either by TAD-HAM (HAM, high-dose araC 1g/m2x6 and mitox 10mg/m2x3) or by HAM-HAM, response and survival did not differ between the two arms in neither age group. In contrast to response and survival between the younger (60-<70y) and older (70+y) age group corresponding differences in the risk profiles were missing. Thus, favorable/intermediate/unfavorable karyotypes accounted for 8% vs 4% / 67% vs 73% / and 25% vs 24% of patients (p=.073); WBC > 20.000/ccm was found in 40% vs 39% (p=.52); LDH > 700U/L was remarkably 26% vs 18% (p=.014), and the day 16 b.m. blasts ≥ 10% accounted for 41% and 41% of patients. Conclusion: Approximately 50% of patients 70 years of age or older benefit from standard or intensive chemotherapy by complete remission which continues after 1 year in about 50% of responders. The inferior overall survival in the patients of 70+ versus those of 60- < 70 years is mainly explained by more frequent early and hypoplastic death (21% vs 12%) (p=.0016) and death with persistent AML (26% vs 18%) (p=.0145); while death in remission (7% vs 6%), relapse rate (50% vs 53%) and death after relapse (21% vs 26%) did not show this trend. In contrast to the important differences in outcome, established risk factors such as cytogenetic groups, WBC, and early blast clearance show concordance between the two age groups. The even lower LDH may support assumptions of older age AML as a less proliferative disease (Appelbaum et al. Blood 107:3481–5,2006). Thus, the hierarchical risk profiles cannot predict the age related outcome beyond 60 years in patients with de-novo AML.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Exome Array Analyses Identify Low-Frequency Germline Variants Associated with Increased Risk of AML in a HLA-Matched Unrelated Donor Blood and Marrow Transplant Population

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 42-42
Author(s):  
Alyssa I. Clay ◽  
Theresa Hahn ◽  
Qianqian Zhu ◽  
Li Yan ◽  
Leah Preus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Association Studies ◽  
Low Frequency ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Advisory Committees ◽  
De Novo Aml ◽  
Normal Cytogenetics

Abstract Both genome wide association studies (GWAS) of common variation and exome wide association studies (EXWAS) of rare variation have successfully identified disease susceptibility variants for a variety of diseases. One GWAS of inherited susceptibility to Acute Myeloid Leukemia (AML) has been conducted, but no EXWAS have been performed to measure risk of AML attributable to low-frequency constitutional genetic variation. We performed the first EXWAS of risk of AML as a nested case-control study in the DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to one-Year mortality after BMT) cohorts. The DISCOVeRY-BMT parent study examined transplant-related mortality in leukemia patients undergoing unrelated donor allogeneic BMT. To identify low frequency variants and genes contributing to increased susceptibility to AML we used genotype data from the Illumina HumanExome BeadChip typed in the DISCOVeRY-BMT cohorts; the HumanExome BeadChip contains 242,901 variants, which are mainly protein-coding variants. The optimal sequence kernel association test (SKAT-O) was used to analyze gene-level associations with risk of AML. These gene-based tests evaluate the cumulative effects of multiple single gene variants on risk of AML. Analyses were performed in all European American AML cases and two subtypes: 1) de novo AML, 2) de novo AML with normal cytogenetics. Models were adjusted for age at transplant and principal components to control for population stratification. For gene-based tests at least 2 variants with minor allele frequency (MAF) ≤ 5%, were required to be present in the gene. This yielded a total of 13,687 genes tested, and a Bonferroni corrected significance level of P<3.65 x 10-6. Association tests were performed in 1,189 AML cases reported to CIBMTR 2000-08 (Cohort 1) and 327 AML cases reported to CIBMTR from 2009-11 (Cohort 2). Controls in Cohorts 1 (n=1,986) and 2 (n= 515) were 10/10 HLA-matched unrelated donors who passed a comprehensive medical exam and deemed healthy. We used metaSKAT to combine Cohorts 1 and 2 and obtain p-values of association with AML. We present the results of gene-level tests significant in both cohorts. The likely pathogenicity of these variants was determined in silico using SIFT, PolyPhen and MutationTaster. Patient characteristics are in Table 1. DNMT3A, on chromosome 2, was associated in the gene-based test with risk of AML (Pmeta=1.70x10-9, Table 2). Three missense variants at MAF <1% comprise both overall AML and de novo AML gene-based association: exm177559 (Asn->Ser), exm177507 (Arg->His), and exm177543 (Arg->Trp). Normal cytogenetics de novo AML gene-based assocations consisted of only 2 of these variants: exm177559 and exm177507 (Table 2). While prevalence of exm177507 is <1% for all AML cases, in de novo AML with normal cytogenetics the MAF was higher at 3%. The other 2 variants had a MAF<1% irrespective of subtype. Somatically, DNMT3A is most frequently mutated in hematologic malignancies, with >30% of de novo AML cases with a normal karyotype and >10% of MDS patients having DNMT3A mutations. Although these are germline gene associations all three of the variants found have been reported somatically in hematologic malignancies. In 200 AML cases from The Cancer Genome Atlas (TCGA) p.R882H (represented as exm177507 on the exome chip) was a frequent somatic mutation (25%). Exm177543 (p.R635W) and exm177559 (p.N501S) are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) as somatic mutations involved in hematopoietic and lymphoid tissue in both cell lines and humans. Exm177507 and exm177543 show evidence of pathogenicity in all three in silico tools, while exm177559 was reported as deleterious and disease causing by Sift and MutationTaster, respectively. Our results show that multiple potentially pathogenic missense germline variants in DNMT3A comprise the gene-based association with AML, specifically de novo AML with normal cytogenetics. Given the functional nature of these variants it is possible germline risk stratification could be informative in determining AML risk, and subsequently development of AML harboring DNMT3A mutations. Confirmation of these findings in additional cohorts could have implications for individualized risk screening, prediction and prognosis. Additional cytogenetic subgroup analyses, including treatment-related AML, are underway. Disclosures Hahn: Novartis: Equity Ownership; NIH: Research Funding. McCarthy:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sucheston-Campbell:NIH/NCI: Research Funding.

Patients Under 50 Years of Age Do Not Present Specific Prognostic Characteristics: An IFM Study in 1897 Patients Under 65 Years of Age.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2837-2837
Author(s):  
Virginie Roland ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Claire Mathiot ◽  
Catherine Charbonnel ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Board Of Directors ◽  
Prognostic Value ◽  
Young Age ◽  
High Dose ◽  
Prognostic Impact ◽  
Prognostic Parameters ◽  
Advisory Committees ◽  
High Dose Melphalan ◽  
The Impact

Abstract Abstract 2837 Poster Board II-813 Age is a critical prognostic factor in many hematological malignancies. The reasons for this major prognostic impact are not univocal. For a large part, its prognostic value is in fact related to the therapy intensity tolerated by the patients. Because of frequent renal, hepatic, cardiac impairments, intensive therapies are not tolerated after 60 or 65 years, leading physicians to dramatically reduce treatment intensity in elderly patients. The question of a specific prognostic value of age in a more homogeneous population is an unresolved issue. In myeloma, it has been suggested that patients under 50 years of age presented more favorable features, explaining the better outcome observed in these patients (Ludwig et al., Blood 2008). However, the population was highly heterogeneous, treated both with conventional and intensive therapeutic strategies. In order to address this question, we reviewed the files of 1897 patients under 65 years of age, homogeneously treated within the IFM with high-dose melphalan, from 2000 to 2007. The median age was 56 years (range=23-65), the sex-ratio male/female was 54%. We addressed the issues of the prognostic impact of young age (<50), but also of older patients (60 to 65). The following prognostic parameters were tested: b2-microglobuline, high creatinine (>177 μmol/l), hypercalcemia, low hemoglobin (<10 g/dl), thrombocytopenia (<130 G/l), ISS, del(13), t(4;14), and del(17p). In the first comparison (<50 vs others), the only statistically different parameters were b2-microglobuline (p=.009) and ISS distribution (p=.004). All the other parameters were not significantly different. Similar results were observed in the second comparison (<60 vs 60-65). Only b2-microglobuline values (p=.0001) and ISS distribution (p<.0001) were different. These differences in b2-microglobuline levels probably reflect the decrease of glomerular filtration with age. We then looked at the impact of age on outcome. We found that patients under 50 years of age displayed a better overall survival than patients between 50 and 65 (p=.007), with no difference in PFS. We also found that patients between 60 and 65 presented a poorer outcome than younger patients (OS, p=0.002, EFS, p=0.01). However, when patients under 50 were compared with those between 50 and 60, no difference was observed, both for OS and EFS. Thus, in conclusion, young age is not a prognostic factor in multiple myeloma. In contrast, older age (60 to 65) remains an adverse prognostic parameters, even in patients treated with high-dose melphalan. Disclosures: Attal: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees.

High Dose Imatinib Induction Therapy (800 mg/day, 6 Months) In Pre-Treated Chronic Phase CML Patients Improves Cytogenetic and Molecular Responses but Does Not Improve Overall and Progression Free Survival – Final Results of the CELSG Phase III CML11 “ISTAHIT” Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2271-2271
Author(s):  
Andreas L Petzer ◽  
Dominic Fong ◽  
Thomas Lion ◽  
Irina Dyagil ◽  
Zvenyslava Masliak ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
De Novo ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 2271 Introduction: Imatinib 400 mg/day represents the current standard treatment for de novo as well as pre-treated CML patients in chronic phase (CP). Recent randomized phase III trials revealed conflicting results concerning the potential higher efficacy of dose-increased imatinib in de novo treated CP-CML. Methods: We here present the final analyses including response data, OS, EFS and PFS of the multicenter, randomised, 2-arm phase III CELSG “ISTAHIT” trial evaluating imatinib high dose (HD) induction (800 mg/day, 6 months) followed by 400 mg/day as maintenance (experimental arm B) compared to continuous imatinib standard dose (400mg/day; arm A) in pre-treated CP CML patients. ClinicalTrials.gov Identifier: NCT0032726. Results: From a total of 243 patients screened for inclusion, 16 patients were not eligible (mainly due to non sufficient numbers of metaphases obtainable from the bone marrow before the start of the study). Of the remaining 227 patients, 113 patients were randomized into arm A and 114 patients into the experimental arm B. Subsequent data are presented as per protocol. No significant differences between treatment groups were observed regarding sex (55.5% female, 44.5% male), age (median: 46.3 years, range 18 –76), Sokal scores at diagnosis (30% low, 41% intermediate, 16% Sokal high risk, 13% unknown) and different pre-treatments, which included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly Ara-C). The median observation time was 673 days. Cytogenetic responses were generally higher in the experimental arm B and revealed statistically significant differences in major cytogenetic responses (MCyR) at 3 and 6 months (month 3: 25.8% arm A, 48.3% arm B, p=0.002; month 6: 41.9% arm A, 58.8% arm B, p=0.029) as well as in complete cytogenetic responses (CCyR) not only during imatinib HD therapy (month 3: 7.5% arm A, 29.9% arm B, p<0.001; month 6: 20.4% arm A, 47.4% arm B, p<0.001) but also thereafter (month 12: 31.8% arm A, 52.9% arm B, p=0.006). The primary endpoint of the study, the achievement of an improved MCyR at 12 month was, however, not significantly different (56.8% arm A, 64.4% arm B). In line with improved cytogenetic responses, major molecular response (MMRIS) rates were also significantly better at 3, 6 and even at 24 months in the HD arm B (month 3: 3.7% arm A, 15.9% arm B, p=0.003; month 6: 9.4% arm A, 34.6% arm B, p<0.001; month 24: 26.5% arm A, 42.5% arm B, p=0.034). Surprisingly, however, this impressing improvement in cytogenetic and molecular remissions in patients achieving high dose imatinib as induction therapy did not translate into a better OS and PFS, both of which were comparable in the two treatment arms (OS: p=0.25; EFS: p=0.37). Moreover, the EFS was even significantly worsened in the experimental arm B (p=0.014). Grade 3/4 non-haematological toxicities during the first 6 months of therapy were comparable, whereas grade 3/4 haematological toxicities were significantly more common in the imatinib HD arm B. Conclusions: Although high dose imatinib induction induces more rapid and higher cytogenetic and molecular remission rates in pre-treated CP CML patients, OS as well as PFS were not improved and EFS was even worsened in the high dose induction arm B. Therefore we conclude that imatinib 400mg/day remains the standard of care for pre-treated CP-CML patients. Disclosures: Petzer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Imatinib 800mg is not licensed as the initial therapy of chronic phase CML. Lion: Novartis: Honoraria, Research Funding. Bogdanovic: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griskevicius: Novartis: Research Funding. Kwakkelstein: Celgene: Employment. Rancati: Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gastl: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wolf: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals BRCA1/2 Containing Complex 3 (BRCC36) Is Recurrently Mutated in AML with t(8;21) and Associated with Increased Sensitivity to Chemotherapy through Impairment of the DNA Damage Repair Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1487-1487
Author(s):  
Tatjana Meyer ◽  
Nikolaus Jahn ◽  
Anna Dolnik ◽  
Peter Paschka ◽  
Verena I. Gaidzik ◽  
...  
Keyword(s):  
Dna Damage ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Dna Damage Repair ◽  
Advisory Committees ◽  
Data Set ◽  
Damage Repair ◽  
De Novo Aml

Abstract Introduction BRCA1/BRCA2-containing complex 3 (BRCC36) is a Lys63-specific deubiquitinating enzyme (DUB) involved in DNA damage repair. Mutations in BRCC36 have been identified in 2-3% of patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). The role of BRCC36 mutations in de novo AML and their impact on DNA damage-inducing cytotoxic chemotherapy sensitivity is not clear. Aim We aimed to determine the incidence of BRCC36 mutations in AML and their impact on outcome and drug sensitivity in vitro. Methods We analyzed the entire coding region of BRCC36 for mutations in 191 AML cases with t(8;21) (q22;q22.1) and 95 cases with inv(16) (p13.1q22) using a customized targeted sequencing panel. Data for de novo AML was derived from The Cancer Genome Atlas Research Network (TCGA) data set (NEJM 2013). Lentiviral CRISPR/Cas9 was used to inactivate BRCC36 in t(8;21)-positive AML cell lines - Kasumi-1 and SKNO-1 - and murine hematopoietic stem and progenitor cells (LSKs). Knockout was confirmed by a cleavage assay as well as Western blot. AML1-ETO-9a was expressed by a retroviral vector. Cell lines and LSK cells were treated with different concentrations of doxorubicin or cytarabine and their viability was assessed seven days post treatment. DNA damage was assessed through phospho-γH2AX staining using flow-cytometry. Results BRCC36 mutations were identified in 7 out of 191 patients (3.7%) with t(8;21) AML and none of 95 patients with inv(16). In the TCGA data set one out of 200 patients (0.5%) with de novo AML had a BRCC36 mutation. This patient had a complex karyotype and would be considered as secondary AML with myelodysplastic-associated changes according to the 2016 WHO classification. Six of the 7 mutations were missense or nonsense mutations that were predicted to be deleterious to BRCC36 function. One mutation affected a splice site at exon 6, resulting in an impaired splicing capability. With intensive standard chemotherapy all patients with BRCC36 mutations achieved a complete remission and had an estimated relapse-free and overall survival of 100% after a median follow up of 4.2 years. Given its role in DNA damage repair, we hypothesized that BRCC36 inactivation sensitizes AML cells to DNA-damage inducing drugs. In order to test this, we generated BRCC36 knockout Kasumi-1 and SKNO-1 cell lines using CRISPR-Cas9. BRCC36 inactivation had no impact on cell growth on either of the cell lines. However, we found that BRCC36 knockout cells were significantly more sensitive to doxorubicin as compared to the parental cells with normal BRCC36. This was accompanied by a significant increase in DNA damage as assessed by phospho-γH2AX in BRCC36 knockout vs control cells after doxorubicin treatment. In contrast, BRCC36 inactivation had no impact on cytarabine sensitivity. We next assessed drug sensitivity in primary murine leukemic cells expressing AML1-ETO-9a. Again, inactivation of BRCC36 resulted in a significant higher sensitivity to doxorubicin but not cytarabine. Conclusion We found BRCC36 to be recurrently mutated in t(8;21)-positive AML Inactivation of BRCC36 was associated with impairment of the DNA damage repair pathway and thus higher sensitivity to DNA damage-inducing chemotherapy. This might be also reflected by the favorable clinical outcome of patients with BRCC36 mutated t(8;21)-positive AML, a finding which has to be confirmed in a large patient cohort. Disclosures Paschka: Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Astex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Bullinger:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Bayer Oncology: Research Funding; Sanofi: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Döhner:Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding.

scholarly journals TP73 Isoforms (TAp73 and ΔNp73) Are Overexpressed in Acute Myeloid Leukemias and Potential Therapeutic Targets to Enhance Anti-Leukemia Activities of Bcl-2 and MDM2 Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2629-2629
Author(s):  
Yuki Nishida ◽  
Jo Ishizawa ◽  
Vivian Ruvolo ◽  
Michael Andreeff
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
De Novo ◽  
Hematopoietic Cells ◽  
Mrna Levels ◽  
Advisory Committees ◽  
Myeloid Leukemias ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Mdm2 Inhibitor

Abstract Background TP73 is one of the TP53 family transcription factors and generates two isoforms, the transactivation p73 (TAp73) and the N-terminally truncated ΔNp73. TAp73 shares a homologous N-terminal activation domain with p53 and has similar pro-apoptotic function to p53. ΔNp73 lacks an activation domain and has activities distinct from TAp73. ΔNp73 has a dominant negative effect on the DNA binding of TAp73 and more importantly, of p53, since the DNA binding domain is homologous with that of TAp73 and highly similar to that of p53. In acute myeloid leukemias (AML), TP73 has been reported to be expressed except in acute promyelocytic leukemias. However, the association of TP73 isoforms with clinical and genetic characteristics and the regulation of the isoforms in AML have not been explored. Results We determined copy numbers of ΔNp73 and TAp73 mRNA levels in 78 AML samples including 31 de novo AML using droplet digital PCR (ddPCR), which allows to determine the absolute quantity of the isoforms expressed, and investigated their clinical and biological relevance. ΔNp73 and TAp73 expression was detected in 93.6% and 98.7% of AML samples at variable levels (mean ± SEM, 10.6 ± 5.0, and 106.6 ± 33.7 copies/µL, for ΔNp73 and TAp73, respectively). ΔNp73 and TAp73 mRNA levels were highly correlated (R2 = 0.72, P < 0.0001). Normal peripheral blood mononuclear cells and CD34+ hematopoietic cells showed little or no ΔNp73 and TAp73 expression (0.09 ± 0.09 and 0.42 ± 0.35 copies/µL, respectively), demonstrating that expression of ΔNp73 and TAp73 is 100 - 1,000 fold higher in AML as compared to normal hematopoietic cells. These data collectively suggests that transcriptional systems of both isoforms in AML cells are abnormally activated. Disease status (de novo or relapsed/refractory) and cytogenetic abnormalities did not correlate with ΔNp73 and TAp73 levels. However, AML with IDH1/2 mutations had 8.5-fold lower ΔNp73 expression than those with wild-type IDH1/2 (1.8 ± 0.8 vs 15.4 ± 7.7 copies/µL, P = 0.0069), with a similar trend for TAp73 (49.0 ± 20.3 vs 138.6 ± 51.4 copies/µL, P = 0.056). For de novo AML samples, those with DNMT3a and NRAS mutations had significantly higher ΔNp73, but not TAp73, than those without these mutations (21.6 ± 18.2 vs 2.5 ± 1.2 copies/µL, P = 0.017 and 5.6 ± 2.5 vs 9.7 ± 8.0 copies/µL, P = 0.047, respectively). These findings suggest that ΔNp73 and TAp73 can be differentially regulated in AML based on mutation status. To further explore the regulation of TP73 isoforms, we used MDM2 inhibitor Nutlin-3a to induce p53 which is a transcriptional inducer of ΔNp73. Indeed, MDM2 inhibition increased p73 protein levels, and knockdown of both TAp73 and ΔNp73 in AML cells enhanced apoptosis induction by Nutlin-3a (specific annexin V induction by 5 uM Nutlin-3a, 21.9 ± 1.3% vs 61.3 ± 5.2%, P = 0.0084 in OCI-AML3 cells with vector control vs Shp73, respectively), possibly due to the silencing of ΔNp73. AML cells with IDH1/2 mutations are more dependent on Bcl-2 than those without (Chan, Nat Med 2015). Intriguingly, (R)-2HG, the oncometabolite of mutant IDH1/2, reduced both TAp73 and ΔNp73 in AML cells and increased susceptibility to the Bcl-2 inhibitor ABT-199. These results imply a potential mechanism that regulates p73 isoforms by histone methylation or other epigenetic modifications in AML. Conclusion Absolute quantitation of TP73 isoforms by ddPCR revealed high expression in AML cells compared to normal hematopoietic cells. The repressed expression of TP73 isoforms in AML cells with IDH1/2 mutations or by the oncometabolite (R)-2HG suggests that epigenetic modifications through (R)-2HG can regulate TP73 transcription and enhance the anti-leukemia effect by Bcl-2 inhibition. Finally, downregulation of TP73 isoforms enhances the efficacy of MDM2 inhibitor in AML, suggesting a potential therapeutic strategy to enhance MDM2 inhibitor-mediated p53 activation. Disclosures Andreeff: Amgen: Consultancy, Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Astra Zeneca: Research Funding; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Reata: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding.

SF3B1 Clone Size Is an Independent Determinant for Overall Survival and Response to Treatment in Patients with Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3001-3001
Author(s):  
Rami S. Komrokji ◽  
David A Sallman ◽  
Najla Al Ali ◽  
Andrew T Kuykendall ◽  
Chetasi Talati ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Value ◽  
Somatic Mutations ◽  
Continuous Variable ◽  
Response To Treatment ◽  
Advisory Committees ◽  
Clone Size ◽  
The Mean ◽  
Baseline Characteristics

Introduction Recurrent somatic mutations (SM) of the splicing factor 3B subunit 1 (SF3B1) are among the most commonly occurring in MDS patients (pts), detected in ~20% of MDS overall, and in approximately 80% of MDS with ring sideroblasts (RS). SF3B1 SM are singularly associated with favorable outcome in MDS in the absence of adverse mutations. Next generation sequencing (NGS) is being increasingly incorporated into the evaluation of MDS pts. However, current results of NGS are reported and interpreted based solely upon the presence or absence of mutations without regard to the mutation allelic burden. Variant allele frequency (VAF) of somatic mutations has been used to reconstruct the clonal architecture in MDS. We examined the impact of SF3B1 VAF on outcomes and response to treatment. Methods We identified all MDS pts informative for SF3B1 mutation status through the Moffitt Cancer Center MDS database. We excluded pts with MDS/MPN or del(5q). We validated the prognostic value of SF3B1 SM in our entire cohort, and then excluded those pts lacking data on SF3B1 VAF. We examined the prognostic value of VAF as a continuous variable using Cox-regression analysis model, and then based on the mean SF3B1 VAF, we divided pts into two groups: VAF ≤ 30 or > 30%. We compared baseline characteristics between the two groups, frequency of other somatic mutations, response to treatment, AML transformation and overall survival (OS). We used the online software (http://molpath.charite.de/cutoff ) (R version 2.15.0), developed for biomarker cutoff determination, to assess the cutoff point of the SF3B1 VAF which best correlates with outcome. The NGS sequencing was performed on an Illumina based platform as part of standard routine clinical assessment. Results Among 763 MDS pts in our database tested for SF3B1 SM, 148 (19.4%) were SF3B1 mutated (MT), of whom 109 (74%) were classified with RS subtypes by WHO 2016 classification. SF3B1 MT was independently associated with better OS after adjusting for IPSS-R, Hazard ratio 0.43 (95% CI .28-.66) (P <.001). The most common SF3B1 hot spot mutation was p.K700E in 47% of cases. The most commonly accompanying gene mutations were: TET-2 (30%), DNMT3A (19%), ASXL-1 (17%), RUNX-1 (9%), and JAK-2 (5%). TP53 MT was detected in 3 pts, and interestingly, 4 pts harbored a second concomitant splicing mutation, 2 pts with SRSF2 MT, U2AF1 and ZRSR2 one each. Seven pts harbored accompanying TET-2 and DNMT3A mutations. Data on VAF was reported in 100 pts. The mean VAF was 30.45%. As a continuous variable, higher VAF was associated with improved OS, HR 0.95 (95% CI .9-.99) (P .024). We divided patients into two groups SF3B1 VAF ≤ 30 or >30 % using the mean VAF as the cutoff. Table-1 summarizes baseline characteristics between the two groups. Interestingly, DNMT3A concomitant MT was significantly more frequent among pts with VAF >30 compared to those with VAF ≤ 30%, 15/55 (27.3%) versus 4/45 (8.9%), (p.023). There was no difference in distribution of other accompanying MT among the 2 groups. The median OS was not reached for those pts with >30% compared to 78 months (95%CI 43-118) for those with VAF ≤ 30% (P .008). The HR for OS was 0.24 (95% CI 0.08-.75) (P .014) for SF3B1 VAF> 30%. There was no difference in the rate of AML transformation 7.3% versus 6.7%, respectively for those with VAF >30 and ≤ 30% respectively, (P 1.0). SF3B1 VAF > 30% was independently associated with favorable OS after adjusting for IPSS-R, HR .29 (95% CI .09-.88) (P .03) The rate of hematological improvement (HI) with erythroid stimulating agents was 53% (21/39) and 43% (9/21) for those with VAF >30 and ≤ 30% respectively, (P .42). The overall response rate to hypomethylating agents (HMA) measured by HI or better was significantly lower in pts with VAF >30 (9%; 2/22) compared to those pts with VAF ≤ 30%. (10/16, 62.6%; P=0.01). The HI rate with lenalidomide was 21.4% (3/14) for those with VAF >30 and 10 % (1/9) for those with VAF ≤ 30%. (P .46) The optimal VAF cutoff related to OS using fit of mixture model was 32.37%, with HR for of 0.26 (95% CI .08-.8) (P .013). Conclusions To our knowledge, this is the first study to demonstrate an impact of SF3B1 clone size on outcome and response to treatment in MDS. Higher VAF > 30% was associated with significantly more prolonged OS, and surprisingly, a lower probability of response to HMA. DNMT3A MT is the only SM significantly associated with higher SF3B1 allele burden, and had no adverse effect on outcome. Table 1. Disclosures Komrokji: Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Kuykendall:Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Celgene: Honoraria. Talati:Agios: Honoraria; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria. Sweet:Incyte: Research Funding; Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Induction with Velcade®/Dexamethasone Partially Overcomes the Poor Prognosis of t(4;14), but Not That of Del(17p), in Young Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 957-957 ◽  
Author(s):  
Hervé Avet Loiseau ◽  
Philippe Moreau ◽  
Claire Mathiot ◽  
Catherine Charbonnel ◽  
Denis Caillot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Board Of Directors ◽  
Poor Prognosis ◽  
Prognostic Value ◽  
Young Patients ◽  
High Dose ◽  
Advisory Committees ◽  
The Poor ◽  
High Dose Melphalan

Abstract Abstract 957 Translocation t(4;14)(p16;q32) has been associated with a poor outcome in multiple myeloma. This poor prognosis has been identified both in patients treated with melphalan-prednisone (MP) and in those treated with high-dose melphalan after a VAD induction. For instance, in 100 patients with t(4;14) treated with VAD and MEL200, the median PFS and OS were 21 months and 41 months, respectively, as compared to 37 months and 65 months for patients lacking the t(4;14) (Moreau et al., Leukemia 2007). Some preliminary studies have suggested that bortezomib (Velcade®) was able to overcome the poor prognosis of the translocation in elderly patients treated with MP-Velcade® (San Miguel et al., NEJM 2008). In order to address this important question, we analyzed 436 patients treated in the IFM, according to the IFM-2005-01 trial, arm B: induction with 4 cycles of Velcade®/Dexamethasone (VD), followed by one or two courses of high-dose melphalan (MEL200). A translocation t(4;14) was observed in 67 of these 436 patients treated with VD (15%), whereas del(17p) was found in 51 patients (11%). Of note, 10 patients presented both the t(4;14) and the del(17p). The median PFS was 25 and 36 months, in patients with or without the t(4;14), respectively (p=0.006). At 3 years, 76% of the patients with t(4;14) were still alive, as compared to 88% of the patients lacking the translocation (p=.003). For comparison, the OS results were respectively 62% (patients with t(4;14)) and 73% (patients lacking the translocation) in patients treated with a VAD induction. Thus, it seems that VD is able to partially overcome the poor prognosis of t(4;14). We also looked at the prognostic value of del(17p) in this series of patients treated with VD. In contrast to the t(4;14) situation, VD was enable to rescue patients with del(17p) (same PFS and OS for patients treated with VD than for those treated with a VAD induction). Thus, this study (by far the largest so far reported) shows that VD as induction before intensification is able to improve the prognosis of patients with t(4;14), but not of those with del(17p). Disclosures: Avet Loiseau: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees.

Improved Response Rate with Bortezomib Consolidation After High Dose Melphalan: First Results of a Nordic Myeloma Study Group Randomized Phase III Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 530-530 ◽  
Author(s):  
Ulf-Henrik Mellqvist ◽  
Jan Westin ◽  
Peter Gimsing ◽  
Oyvind Hjertner ◽  
Stig Lenhoff ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Response Rate ◽  
Single Agent ◽  
Phase Iii ◽  
High Dose ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
The Mean ◽  
High Dose Melphalan ◽  
Grade Iii

Abstract Abstract 530 An open, multi-center, randomized phase III trial performed by the Nordic Myeloma Study Group (NMSG) was designed to explore the effect of a 21-week consolidation period of single agent bortezomib, given during months 3-8 after ASCT. Primary end-point was event free survival and secondary end-points were response rate, toxicity, overall survival, quality of life and cost utility. Between November 2005 and April 2009 404 patients were included, 372 of whom were randomized. This report comprises preliminary data concerning feasibility, toxicity and response rate for the initial 299 randomized patients. Patients were randomized 3 months post ASCT to either no consolidation therapy (current standard in Scandinavia), or to a period of bortezomib consolidation. Initial treatment before ASCT was optional. Patients were stratified for single or double ASCT. Bortezomib was given in a dose of 1.3 mg/m2 twice weekly (days 1, 4, 8 and 11) in a 3 week schedule for the first 2 cycles. In the following four cycles, bortezomib was given once weekly (days 1, 8 and 15) in a 4 week schedule, in total 20 injections over 21 weeks. Before each dose of study drug, the patients were evaluated for possible toxicities. Baseline characteristics were well balanced between the 149 patients in the bortezomib group and the 150 in the control group. All analyses were performed on an intention to treat basis. The mean number of bortezomib injections was 15, median 19 of optimal 20. The mean total dose given was 82 %, median 90 %, of the planned dose. Thirty-one patients (21 %) had to reduce the dose to zero for one cycle or more, mainly due to neuropathy, 11 patients, or progression, 8 patients. Hematological toxicity according to CTC included neutropenia grade ≥ III in 33 patients (22 %), thrombocytopenia grade ≥ III in 14 patients (9 %). Neurological pain grade ≥ III was seen in 7 patients (5 %). Sensory neuropathy grade ' III was seen in 5 patients (3 %). A significant difference in improvement of response was noted between the two arms. At the time of randomization the proportion of CR/nCR was 23 % for patients in the bortezomib arm and 21 % in the control arm. However, when measured six months after randomization (9 months after ASCT), the proportion of CR/nCR was 54 % in the bortezomib group versus 35 % for the controls, p < 0.005. The proportion of patients improving their response from PR to CR/nCR was 20 % and 12 % for the bortezomib and control groups respectively, p = 0.06 NS. The proportion of patients who relapsed during the initial 6 month observation period did differ significantly, 1 % versus 6 %, p<0.05. Our results indicate that consolidation with bortezomib given as a single agent is feasible and does improve treatment response after ASCT. Disclosures: Mellqvist: Jansen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Johnson and Johnson: Research Funding. Off Label Use: Bortezomib. Consolidation therapy after high dose melphalan.. Westin:Celgene: Membership on an entity's Board of Directors or advisory committees. Gimsing:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees; Schering-Plough: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Laane:Schering-Plough: Membership on an entity's Board of Directors or advisory committees. Remes:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Waage:Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees.

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